Singlet oxygen exerts concentration-dependent effects on biological systems. At elevated levels, it contributes to oxidative damage and cell death. However, at sub-toxic concentrations, singlet oxygen triggers a hormetic response, activating intrinsic cellular defense mechanisms by upregulation of antioxidant enzymes, redox-sensitive signaling, immune modulation, and autophagic processes. This hormetic response promotes resilience, repair, and redox homeostasis. [i]

This chapter outlines the molecular pathways and systems influenced by low-dose singlet oxygen, providing a mechanistic foundation for its Physiological potential.

1.1. Nrf2-Keap1 Pathway, Sirt6 and ARE Gene Activation

One of the primary oxidative stress sensors activated by singlet oxygen is Nrf2 (Nuclear factor erythroid 2–related factor 2),[ii] which is a transcription factor that regulates the antioxidant defense system through the Nrf2-Keap1 pathway. A homodimer of Keap1 (Kelch-like ECH-associated protein 1) inhibits Nrf2 transcriptional activity by binding to its evolutionarily conserved N-terminal regulatory domain, thereby targeting Nrf2 for ubiquitin-proteasome-dependent degradation.[iii] Exposure to ROS or lipid-derived secondary messengers (such as 4-HNE), generated via the oxidation of primary membrane targets (as described in section ‎4.3), oxidize specific cysteine residues on Keap1. This triggers a conformational change in the Keap1 homodimer, disrupting its inhibitory ‘clamp’ on Nrf2 and preventing further ubiquitination and degradation. Freed Nrf2 translocates to the nucleus, where it binds to antioxidant response elements (AREs) in the promoter regions of detoxification and cytoprotective genes, promoting their transcription.

SIRT6, a NAD⁺-dependent histone deacetylase, supports the antioxidant response by enhancing Nrf2 stability and facilitating access to the regulatory regions of antioxidant genes. Upon oxidative stress, SIRT6 expression increases and contributes to Nrf2 activation by reducing its degradation, promoting its accumulation in the nucleus,[iv] and enabling robust transcription of antioxidant targets. SIRT6 also modulates chromatin structure, promoting an open configuration at specific Nrf2-responsive loci, which enhances recruitment of transcriptional machinery and efficient expression of antioxidant genes to counteract oxidative damage.[v]

Major downstream targets include:

1.1.1.             Glutathione synthesis

Nrf2 upregulates the catalytic (GCLC) and modifier (GCLM) subunits of glutamate-cysteine ligase, the rate-limiting enzyme in glutathione (GSH) biosynthesis.[vi],[vii] GSH is a central redox buffer that neutralizes hydrogen peroxide, lipid peroxides,[viii] and electrophilic agents via enzymatic and non-enzymatic reactions.[ix] Critically, it maintains cellular proteins in their reduced thiol form, preventing aberrant disulfide cross-linking that can impair enzymatic activity and cellular signaling.[x] By preserving this thiol-disulfide balance, GSH supports proper protein folding, redox-sensitive signal regulation, and cytoskeletal organization.[xi]

Importantly, Nrf2-dependent enhancement of GSH synthesis also contributes to tissue repair mechanisms. Elevated GSH levels facilitate fibroblast migration, reduce oxidative delay in re-epithelialization, and accelerate wound closure under inflammatory conditions.[xii] Thus, GSH not only buffers oxidative insults but orchestrates a redox environment conducive to regeneration.

1.1.2.             Detoxification

Nrf2 activation leads to the upregulation of multiple Phase II detoxifying enzymes, including NAD(P)H quinone oxidoreductase 1 (NQO1), heme oxygenase-1 (HO-1), and peroxiredoxins (PRDXs). These enzymes mitigate oxidative and electrophilic stress not by directly scavenging ROS, but by converting reactive intermediates into less harmful, excretable forms.

• NQO1 catalyzes the two-electron reduction of quinones to hydroquinones, thereby preventing redox cycling and ROS amplification.[xiii]
• HO-1 degrades pro-oxidant heme into biliverdin, free iron, and carbon monoxide; biliverdin and its product bilirubin act as potent endogenous antioxidants, while carbon monoxide exhibits anti-inflammatory effects.[xiv]
• Peroxiredoxins (PRDX1–6) catalyze the reduction of peroxides and modulate redox signaling by buffering fluctuations in H₂O₂ levels.[xv]

Together, these enzymes form a highly inducible frontline defense that complements glutathione systems and enhances the cell’s capacity to detoxify harmful byproducts of oxidative stress and inflammation.

1.1.3.             Redox regulation and lipid-derived mediators

Nrf2 supports redox homeostasis not only through antioxidant enzymes but also regulating enzymes that maintain thiol integrity and modulate lipid signaling. A core component of this system includes thioredoxin reductase 1 (TXNRD1) and superoxide dismutases (SOD1–3). SODs catalyse the dismutation of superoxide anions into hydrogen peroxide,[xvi] a less reactive species that is further detoxified by catalase[xvii] or glutathione peroxidase. TXNRD1 maintains thioredoxin in its reduced form, enabling it to reduce disulfide bonds in proteins, thus repairing them, and ensuring redox signal fidelity.[xviii]

Additionally, Nrf2 influences the metabolism of oxidized lipids through enzymes like ALOX15 (Arachidonate 15-lipoxygenase), which converts polyunsaturated fatty acids into mediators such as 15-HETE and lipoxins. These bioactive lipids help resolve inflammation, promote macrophage polarization toward anti-inflammatory phenotypes, and regulate redox-sensitive immune responses. [xix]

To complement its antioxidant functions, Nrf2 also supports proteasome activity under stress conditions by promoting the transcription of specific proteasome subunits. This enhances both 20S and 26S proteasomal capacity, which is especially important when misfolded or oxidized proteins accumulate.[xx] In addition, Nrf2-driven adaptation enhances the efficiency of ATP-independent degradation by the 20S core proteasome — a critical pathway in cells where autophagic function or ATP supply is limited.[xxi]

Such Nrf2–proteasome interplay is particularly relevant in non-dividing or long-lived cells, including muscle fibers and neurons, where sustained proteotoxic stress can disrupt cellular function.

In parallel, oxidative stress and thiol imbalance can trigger protein unfolding and aggregation. Nrf2 indirectly supports proteostasis by sustaining redox conditions that favor proper protein folding and by coordinating with heat shock proteins (HSPs), which refold or triage misfolded proteins. Heat shock protein 70 (HSP70)[xxii] assists in protein folding and prevents aggregation under stress, activating transcription factor 4 (ATF4)[xxiii] that coordinates the integrated stress response, regulating redox balance and cell survival. This redox–chaperone axis is particularly important in long-lived cells, such as neurons, where oxidative injury can destabilize protein structure and impair cellular function.[xxiv]

Through these pathways, Nrf2-linked redox systems contribute broadly to cellular stability in the face of oxidative stress. In redox-sensitive tissues like the nervous[xxv] and cardiovascular[xxvi] systems, these mechanisms support resilience by modulating stress signaling, protecting structural proteins, and promoting inflammatory resolution,[xxvii] without relying on direct ROS scavenging alone.

1.1.4.             Mitochondrial regulation

Nrf2 contributes to mitochondrial health and metabolic adaptation under oxidative stress by regulating transcriptional programs that coordinate mitochondrial biogenesis, quality control, and antioxidant defense. Key among these is PGC-1α (Peroxisome proliferator-activated receptor gamma coactivator 1-alpha), a central coactivator that stimulates the expression of nuclear respiratory factors (NRF1, NRF2/GABPA)[xxviii] and mitochondrial transcription factor A (TFAM), together promoting mitochondrial DNA replication and respiratory enzyme synthesis.[xxix]

Mitochondrial adaptation to low-dose singlet oxygen is not a result of direct molecular interaction, but rather a coordinated response to the membrane-initiated redox relay described in section ‎4.3. The secondary messengers generated at the plasma interface (e.g., 4-HNE) diffuse through the cytosol to interact with mitochondrial-resident proteins, such as DJ-1 (PARK7).

Acting as a redox sentinel, DJ-1 stabilizes the Nrf2 protein by further inhibiting its Keap1-mediated degradation, specifically shielding the mitochondria from potential oxidative injury.[xxx]  This ‘mitohormetic’ signaling triggers a transcriptional program led by PGC-1α, which coordinates with SIRT6 and Nrf2 to promote mitochondrial biogenesis and enhance the expression of mitochondrial-specific antioxidants like SOD2 and GPX4,  which are critical in detoxifying mitochondrial ROS and preventing lipid peroxidation.[xxxi]

In addition to the Nrf2–DJ-1 axis, the sirtuin family member SIRT6 serves as a critical co-regulator of mitochondrial homeostasis and metabolic resilience under oxidative stress.[xxxii] As mentioned above, SIRT6 functions as a “redox-sensor” that can directly interact with and stabilize Nrf2, thereby amplifying the expression of the aforementioned ARE-dependent genes, such as HO-1 and NQO1.⁴⁰ Beyond its nuclear roles, SIRT6 is essential for maintaining mitochondrial quality control by preventing mitochondrial fragmentation and supporting efficient ATP production, which is a process that aligns with the activity of PGC-1α and AMPK in responding to transient hormetic signals.^67,[xxxiii] By coordinating nuclear antioxidant defenses with mitochondrial bioenergetics, SIRT6 ensures that low-dose singlet oxygen exposure results in metabolic adaptation rather than energetic failure, reinforcing the systemic resilience characteristic of redox hormesis.[xxxiv]

By aligning nuclear antioxidant defenses with mitochondrial bioenergetics, this relay ensures that the cell increases its ATP production efficiency and respiratory capacity. Consequently, the transient biophysical trigger at the membrane is translated into long-term metabolic resilience, preventing mitochondrial fragmentation and ensuring energetic homeostasis during periods of physiological stress.

1.1.5.             Anti-Inflammatory and Cytoprotective Roles of Nrf2 [xxxv]

In addition to regulating antioxidant gene expression, Nrf2 plays a pivotal role in modulating inflammation. Upon activation, Nrf2 suppresses the expression of pro-inflammatory cytokines such as IL-6, TNF-α, and IL-1β by interfering with NF-κB signaling and by inducing anti-inflammatory mediators like HO-1 and ferritin.

The anti-inflammatory efficacy of Nrf2 is significantly augmented by its crosstalk with SIRT6, that serves as a potent repressor of pro-inflammatory gene expression.[xxxvi] While Nrf2 suppresses the transcription of cytokines, SIRT6 acts directly at the chromatin level by deacetylating Histone H3 at the promoters of NF-κB target genes. This ‘epigenetic silencing’ effectively dampens the inflammatory response even in the presence of persistent stress signals. Under hormetic conditions, low-dose singlet oxygen may enhance the stability of both Nrf2 and SIRT6, creating a synergistic anti-inflammatory axis that prevents the transition from acute, protective signaling to chronic, systemic inflammation.[xxxvii] This coordinated regulation is particularly relevant in age-related ‘inflammaging’, where the concurrent decline of Nrf2 and SIRT6 otherwise leaves tissues vulnerable to cytokine-mediated damage.

This modulation reduces systemic inflammation, limits immune overactivation, and contributes to tissue protection in conditions such as:

• Autoimmune diseases:[xxxviii] Nrf2 activation mitigates cytokine storms (e.g., in lupus or multiple sclerosis).
• Metabolic syndromes:[xxxix] Suppresses inflammation in diabetes and obesity.
• Pulmonary disorders: [xl] Reduces airway inflammation in asthma and COPD.
• Neurodegeneration:[xli] Damps neuroinflammation via microglial modulation.

Thus, as summarized in Table 3, Nrf2 serves as a dual-function regulator, both antioxidant and anti-inflammatory, essential to the hormetic adaptation elicited by singlet oxygen.

Table 3 Integrated Defense Systems Regulated by the Nrf2-ARE Axis

1.2. MAPK Signaling and Oxidative Stress Sensors

Beyond the Nrf2-Keap1 pathway, the membrane-initiated relay activates several additional signaling pathways involved in stress response, inflammation regulation, cell death and repair mechanisms. These pathways ensure that cells maintain homeostasis, limit damage, and initiate adaptive processes during oxidative stress.

For example, the p53 tumor suppressor protein,[xlii] a key regulator of DNA repair and apoptosis, is activated in response to oxidative stress, helping cells manage or eliminate damage. Similarly, the MAPK family consists of several key protein kinases, including ERK1/2 (extracellular signal-regulated kinase), JNK (c-Jun N-terminal kinase), and p38 MAPK, which are activated through upstream stress sensors, including oxidative modifications of receptor proteins, mitochondrial ROS signaling, and changes in redox balance (Table 4).[xliii]

• The ERK1/2 pathway is central to the regenerative effects of low-dose therapy. By promoting fibroblast proliferation and keratinocyte migration,[xliv] this pathway orchestrates the structural remodeling of the extracellular matrix, facilitating the ‘smoothing’ of tissue and accelerated closure of wounds.
• While JNK and p38 are often associated with apoptosis at high ROS concentrations, under hormetic (low-dose) conditions, they act as metabolic rheostats. They modulate the activity of transcription factors involved in the integrated stress response, ensuring that the cell prioritizes repair over programmed cell death.^78,[xlv]

Through this multi-layered signaling network, the cell converts the initial biophysical trigger at the membrane into a sophisticated ‘decision-making’ process that favors repair, survival, and structural rejuvenation.

Table 4 MAPK Functional Specialization

1.3. Autophagy and Cell Fate Regulation

The “Relay” logic holds that the cell does not wait for internal damage to reach a critical mass; instead, the biophysical trigger at the membrane initiates a preemptive “quality control” protocol, with the capacity to promote either cell survival or cell death. This duality is mediated through its ability to induce autophagy or apoptosis, two distinct yet interconnected processes that are often activated sequentially in response to stress. Autophagy, a highly conserved mechanism present in all eukaryotes, from unicellular organisms to mammals,[xlvi] is responsible for selectively degrading oxidized and damaged intracellular components, such as proteins and organelles (particularly mitochondria), via the lysosomal pathway. This process is essential for preserving cellular integrity and function during mild stress.[xlvii]  

1.3.1.             Oxidative Stress Intensity as a Determinant of Cell Fate

The outcome of oxidative stress is not binary but graded, depending on its intensity, duration, and localization.33^,[xlviii]^,[xlix] At low to moderate levels, oxidative stress initiates adaptive responses, including Nrf2 activation and the induction of autophagy, enabling cells to restore homeostasis. In contrast, sustained or intense oxidative insults can overwhelm these defenses, tipping the balance toward apoptosis or necrosis (Figure 4).

As established in earlier sections, singlet oxygen acts as a metabolic rheostat. At low hormetic doses, secondary messengers (like 4-HNE) and redox-sensitive kinases (ASK1) favor the induction of Autophagy, a survival-oriented process that clears the “biological clutter” before it can trigger Apoptosis (cell death).[l] In addition, A key non-transcriptional effect of singlet oxygen is the oxidative modification of the Bcl-2 protein. This disruption releases Beclin-1, the “master switch” for autophagy initiation, allowing for rapid cellular response that bypasses the need for slower nuclear transcription. ^82,83,[li]

Figure 4 Schematic representation of the cellular decision-making process in response to varying intensities of singlet oxygen-induced stress. (Left) The Hormetic Zone: Under low-intensity oxidative conditions, the membrane-initiated relay activates a transient and moderate signaling surge through ASK1 and JNK/p38 MAPKs. This level of activation favors the stabilization of Nrf2 and the induction of Autophagy, specifically Mitophagy and CMA, to selectively sequester and degrade oxidatively damaged organelles and proteins. This ‘quality control’ phase promotes cellular recalibration and homeostatic recovery. (Center) The Rheostat Switch: The ASK1-JNK axis functions as a molecular rheostat, where the duration and amplitude of the oxidative signal determine the functional outcome. (Right) The Distress Zone: Under conditions of high-intensity or chronic oxidative stress, the sustained over-activation of these kinases leads to the phosphorylation-dependent dissociation of the Bcl-2–Beclin-1 complex and the subsequent release of pro-apoptotic factors, such as Cytochrome c. This shifts the cellular fate from survival-oriented cleanup to Caspase-dependent Apoptosis, ensuring the programmed elimination of irreversibly damaged cells. Together, these pathways illustrate the graded, non-binary nature of the stress response, where controlled oxidation acts as a primary messenger for survival.

Furthermore, singlet oxygen can influence the hypoxia-inducible factor 1 (HIF-1) pathway, which plays a pivotal role in cellular responses to low oxygen levels.[lii] While the HIF-1 pathway is primarily known for regulating genes that adapt to hypoxic conditions, it also intersects with autophagy mechanisms.

These immediate oxidative modifications allow singlet oxygen to act as a first messenger in stress adaptation, influencing the balance between repair and cell death independently of transcription. This reinforces the concept of oxidative stress as a rheostat, where controlled oxidation promotes survival pathways, while excess shifts the balance toward irreversible damage.

1.3.2.             Subtypes of Autophagy

The primary forms of autophagy implicated are macroautophagy, mitophagy, and chaperone-mediated autophagy (CMA), each targeting distinct cellular liabilities within the cell.

Macroautophagy (often just referred to as autophagy) is responsible for bulk degradation of damaged or oxidized cytoplasmic material. Upon low-level oxidative stress, singlet oxygen can trigger macroautophagy by oxidizing redox-sensitive regulators, enabling the sequestration of dysfunctional proteins and organelles into autophagosomes. Although traditionally viewed as non-selective, macroautophagy often targets specific substrates based on oxidative modification patterns.^82,[liii]

Mitophagy, a specialized subset of macroautophagy, mitophagy, specifically eliminates damaged or dysfunctional mitochondria. Mitochondria are central to cellular energy production. However, as organisms age, mitochondrial DNA (mtDNA) accumulates mutations, leading to decreased efficiency in the electron transport chain and increased production of ROS. The increased oxidative stress may further damage cellular components, thus accelerating aging and age-related diseases,[liv] including neurodegenerative disorders, [lv] cardiovascular diseases, [lvi] and metabolic syndromes[lvii]. This underscores the importance of inducing mitophagy to remove these compromised organelles and prevent further ROS production. Two mitophagy pathways have been identified. In one pathway, JNK influences mitophagy through the modulation of PINK1/Parkin Pathway, as JNK activation can promote the stabilization of PINK1 on the outer membrane of depolarized mitochondria, facilitating the recruitment of Parkin, an E3 ubiquitin ligase. Parkin ubiquitinates mitochondrial proteins, marking the mitochondria for autophagic degradation.[lviii]

Independently of the PINK/Parkin pathway, mitophagy can also occur through the phosphorylation of FUNDC1.[lix] JNK phosphorylates FUNDC1, a mitochondrial receptor, which enhances its binding affinity for LC3 or other autophagy proteins, facilitating the engulfment of damaged mitochondria by autophagosomes.

By utilizing both the PINK1/Parkin (ubiquitin-dependent) and FUNDC1 (receptor-dependent) pathways, the cell ensures that ‘leaky’ mitochondria, those with mutated mtDNA or inefficient electron transport, are selectively removed. This prevents the energetic failure typically seen in aging and metabolic syndromes, effectively ‘rejuvenating’ the cellular power supply.

Chaperone-Mediated Autophagy (CMA)[lx] is a form of autophagy that selectively degrades soluble cytosolic proteins containing the KFERQ-like pentapeptide motif. Under oxidative stress, oxidized proteins are recognized by chaperones and translocated directly into lysosomes for degradation. This process helps in the removal of oxidatively damaged proteins, thereby maintaining protein quality control.[lxi] JNK signaling has been implicated in modulating this pathway as it may influence the expression of chaperone proteins under mild oxidative conditions, thereby enhancing the selective degradation of oxidized cytosolic proteins. While the direct involvement of JNK in CMA regulation is less clear, oxidative stress may upregulate the expression of LAMP-2A,[lxii] the lysosomal receptor essential for CMA substrate translocation. Increased LAMP-2A levels enhance the cell’s capacity to degrade oxidized proteins via CMA.[lxiii] In addition, stress conditions can affect the activity of Hsc70,^{Error! Bookmark not defined.} the cytosolic chaperone that recognizes and delivers substrates to LAMP-2A. Modulation of Hsc70 activity influences the efficiency of CMA.

Table 5 Specialized Autophagic Pathways Triggered by Oxidative Stress

Together, these autophagic pathways (Table 5) offer an orchestrated response that favors selective clearance and functional recovery rather than indiscriminate degradation, a hallmark of the hormetic action of singlet oxygen.

1.3.3.             Biological Implications of Autophagy

Autophagy pathway activation has been shown to prevent stress-induced tissue and organ injury. Beyond its immediate cytoprotective function, autophagy contributes to a wide range of systemic adaptations relevant to stress resilience, aging, immunity, and tissue homeostasis (Table 6).

Table 6 Systemic Resilience via the Autophagic Relay

1.3.3.1.        Systemic Functions: Immunity, Inflammation, and Aging

Autophagy plays a multifaceted role in immune homeostasis. It mitigates chronic inflammation by degrading damaged organelles and oxidized macromolecules, thereby limiting the passive release of damage-associated molecular patterns (DAMPs)[lxiv] such as mitochondrial DNA, ATP, and oxidized proteins. This suppression of DAMP leakage helps prevent uncontrolled inflammasome activation and cytokine release. Conversely, under certain stress conditions, autophagy may also actively facilitate the secretion of select DAMPs, such as HMGB1, through non-classical pathways- initiating a context-dependent immunomodulatory feedback loop that can further enhance autophagy.[lxv]

In addition, autophagy functions as a key regulator of immune responses. It plays a crucial role in defending against intracellular pathogens by sequestering and degrading them through a process known as xenophagy,[lxvi] as well as contributing to antigen processing and presentation via MHC class II molecules, supports T cell development and homeostasis, and helps shape adaptive immune responses.

Through these mechanisms, autophagy serves as a multi-layered system that integrates microbial defense, inflammation control, and immune regulation, highlighting its potential as a therapeutic target for infectious, inflammatory, and autoimmune diseases.[lxvii]

In the aging context, basal autophagy levels decline, contributing to the accumulation of cellular damage. The age-related decline in basal autophagy is closely linked to the waning expression of the longevity-associated sirtuin, SIRT6. SIRT6 serves as a vital molecular switch that promotes autophagic flux by modulating the AMPK–mTOR signaling axis and increasing the expression of key autophagy-related genes (ATGs). Under conditions of mild oxidative stress, such as those induced by low-dose singlet oxygen, SIRT6 can be activated to facilitate the clearance of damaged organelles and proteotoxic aggregates that otherwise accumulate during senescence. By transiently restoring SIRT6-mediated autophagy, singlet oxygen may help ‘rejuvenate’ the cellular clearing apparatus, thereby preserving stem cell function and enhancing systemic resilience against age-related degeneration.^{67,69,[lxviii]} Autophagy also preserves stem cell function across multiple tissues, including muscle, liver, and hematopoietic systems, by maintaining redox and mitochondrial integrity.[lxix]

1.3.3.2.        Nervous System: Maintaining Proteostasis and Synaptic Health

Neuronal cells are especially vulnerable to oxidative damage due to their high metabolic demands and limited regenerative capacity. Autophagy helps remove dysfunctional mitochondria (mitophagy) and protein aggregates, maintaining proteostasis and preventing excitotoxicity. In the context of singlet oxygen exposure, selective autophagy helps prevent the accumulation of neurotoxic proteins such as α-synuclein and phosphorylated tau, processes implicated in neurodegenerative diseases[lxx]^,[lxxi] including Parkinson’s and Alzheimer’s[lxxii]. Moreover, autophagy contributes to neural development and synaptic plasticity, influencing learning and memory processes.¹⁰⁶ Dysregulation of autophagy with aging or chronic oxidative stress can exacerbate excitotoxicity and synaptic loss, while controlled activation may confer neuroprotection.[lxxiii]

1.3.3.3.        Skin: Barrier Maintenance and Oxidative Detoxification

The skin can be viewed as a dynamic immuno-cutaneous ecosystem, where autophagy within skin cells plays a crucial role in preserving immune balance. [lxxiv] As the body’s largest interface with the environment, the skin is chronically exposed to environmental stressors such as ultraviolet (UV) radiation, pathogens, and oxidants, stressors that can damage keratinocytes, lipids, and extracellular matrix proteins. Autophagy plays a central role in removing harmful intracellular components, maintain cellular homeostasis, and prevent inflammation and premature aging.[lxxv]

A wide range of resident immune cells inhabit the skin, including Langerhans cells, dermal dendritic cells, macrophages, mast cells, and tissue-resident T cells. These immune cells are in ongoing communication with keratinocytes and other structural cells of the skin, collaboratively detecting and responding to pathogens, tumors, allergens, and autoantigens through intercellular signaling involving DAMPs and pathogen-associated molecular patterns (PAMPs) [lxxvi].

• Keratinocytes, the predominant cells of the epidermis, are particularly active in this process. In response to UV exposure, oxidative stress, or physical injury, they release DAMPs such as HMGB1, ATP, IL-1α, uric acid, and heat shock proteins. They also express pattern recognition receptors (PRRs), including Toll-like receptors (TLRs) and NOD-like receptors,[lxxvii] to identify microbial PAMPs like bacterial lipopolysaccharide (LPS), viral RNA, or fungal β-glucans.¹¹¹
• Dermal fibroblasts also serve as key immune modulators. They detect both DAMPs and PAMPs in response to tissue stress, contributing to immune cell recruitment and activation. Importantly, fibroblasts exhibit considerable heterogeneity, with specific subpopulations involved in immune surveillance, epithelial–immune cell communication and sustaining chronic skin inflammation.[lxxviii]
• Melanocytes, while less studied in this context, can respond to PAMPs by producing cytokines and chemokines, and may also release DAMPs under oxidative stress, a process implicated in inflammatory skin conditions such as vitiligo.[lxxix]

It has been shown that autophagy supports the function of key skin cells types, including keratinocytes, melanocytes, and immune cells, by regulating inflammation, promoting cell differentiation, and protecting against infection. In dermal fibroblasts, autophagy plays a critical role in modulating responses to DAMPs and PAMPs, limiting excessive immune activation through the degradation of damaged organelles and the regulation of cytokine release.¹¹³ In keratinocytes and epidermal stem cells, autophagy helps preserve skin renewal and barrier function, thereby reducing pathogen penetration and lowering the activation threshold of resident immune cells. In melanocytes, autophagy contributes to pigmentation homeostasis by regulating melanin distribution.[lxxx]

These functions highlight autophagy’s essential role in skin wound healing across all key phases: hemostasis, inflammation, proliferation, and remodeling.[lxxxi] It promotes keratinocyte proliferation and migration, drives fibroblast activation and differentiation, supports new blood vessel formation (angiogenesis), and helps clear damaged organelles and inflammatory mediators, supporting efficient tissue repair and re-epithelialization. Additionally, autophagy contributes to immune balance by regulating macrophage and neutrophil activity and supporting resolution of inflammation.

When autophagy is disrupted, it can lead to cellular senescence, chronic inflammation, impaired wound healing, and increased risk of pathological scarring or skin cancers. Dysregulated autophagy is also associated with immune-related skin disorders, including atopic dermatitis, psoriasis, and alopecia areata. ¹⁰⁹

It can be concluded that the controlled induction of autophagy may offer a more effective, targeted approach for managing chronic skin conditions. It is also a promising therapeutic target for enhancing wound healing outcomes, treating skin aging and related disorders.

1.3.3.4.        Lung: Adaptive Remodeling and Inflammation Control

Autophagy plays a multifaceted role in lung injury and repair by supporting tissue-specific responses such as alveolar regeneration, redox homeostasis, and immune modulation. In particular, autophagy is essential for alveolar type 2 (AT2) progenitor cell–mediated regeneration following lung injury.[lxxxii] By promoting glucose, limiting lipid accumulation, and reducing oxidative stress, autophagy supports AT2 proliferation and epithelial barrier restoration.

In acute lung injury (ALI), autophagy interacts with the Nrf2 Nrf2 pathway to enhance antioxidant defense:[lxxxiii] by degrading the Nrf2 inhibitor Keap1, autophagy facilitates Nrf2 stabilization, contributing to protection against oxidative inflammation and preserving alveolar function. However, as in other tissues, the context and extent of autophagy determine its protective vs. detrimental effects

This balance becomes especially relevant in sepsis-induced lung injury, where autophagy maintains epithelial barrier integrity and regulates immune cell activity. Excessive or prolonged autophagic activation under systemic inflammatory stress may contribute to tissue damage and impaired resolution.[lxxxiv]

Autophagy also contributes to the pathogenesis of chronic pulmonary diseases:

• In chronic obstructive pulmonary disease (COPD), impaired autophagy disrupts mitochondrial clearance, while excessive autophagy can lead to epithelial cell death and persistent inflammation. Both patterns contribute to tissue destruction and reduced regenerative potential. [lxxxv]^,[lxxxvi]
• In idiopathic pulmonary fibrosis (IPF), deregulated autophagy in epithelial and mesenchymal cells is associated with aberrant fibroblast activation and extracellular matrix accumulation, promoting fibrosis.[lxxxvii]^,[lxxxviii]
• In asthma, autophagy modulates immune cell recruitment and cytokine release, influencing airway inflammation and remodeling. Dysregulated autophagy has been linked to enhanced airway hyperresponsiveness and resistance to corticosteroids.^120,[lxxxix]

Taken together, these findings underscore the context-dependent roles of autophagy in pulmonary health. Targeting autophagic signaling in a cell-type- and disease-specific manner may open new therapeutic avenues for both acute and chronic lung diseases.

1.3.3.5.        Cardiovascular System: Cardioprotection and Vascular Homeostasis

Autophagy plays a critical role in maintaining cardiovascular health by supporting the turnover of damaged cellular components, particularly under stress conditions such as ischemia.[xc] In cardiac tissues, this process reduces myocardial injury, facilitates tissue remodeling, and promotes recovery after oxidative or mechanical insults. ¹³⁹

When autophagy is defective or insufficient, cardiomyocytes accumulate dysfunctional mitochondria, misfolded proteins, and oxidative byproducts, [xci] which are hallmarks of cardiac aging and pathology. These impairments contribute to the progression of cardiomyopathies and heart failure. Mitophagy, the targeted removal of damaged mitochondria, is especially vital in the heart, where cells contain a high density of mitochondria and are constantly subjected to high oxidative and metabolic demands. By clearing depolarized mitochondria, mitophagy limits excessive ROS production and protects against ischemia–reperfusion injury. [xcii]

In the vascular system, autophagy also serves as a key homeostatic mechanism. Endothelial cells rely on basal autophagic activity to preserve nitric oxide signaling, limit vascular inflammation, and prevent atherogenesis. When this regulatory process is impaired, either by aging, chronic inflammation, or external oxidative stimuli such as singlet oxygen, vascular dysfunction and pro-atherogenic changes may ensue. ¹²⁵

Importantly, the Nrf2–autophagy axis integrates redox-sensitive signaling with lipid metabolism and immune regulation, offering an additional layer of protection against oxidative and inflammatory stressors. Through this pathway, low-level singlet oxygen may promote adaptive remodeling and preserve vascular tone without triggering damaging oxidative overload. [xciii]

Together, these findings position autophagy as a central mechanism in cardiovascular resilience, mediating both cardiac and vascular adaptations to oxidative stress, including that induced by singlet oxygen exposure.

1.3.3.6.        Skeletal Muscle: Quality Control and Adaptation to Stress

Autophagy maintains skeletal muscle homeostasis by removing dysfunctional proteins and organelles, particularly mitochondria, which is essential for preserving muscle mass, contractile performance, and metabolic adaptability. Mitophagy, the selective degradation of damaged mitochondria, plays a particularly critical role in muscle fibers, where high oxidative load and metabolic turnover necessitate constant mitochondrial quality control. Impairments in this process have been associated with various myopathies, including sarcopenia, muscular dystrophies, and cancer-associated cachexia, as accumulation of dysfunctional mitochondria and protein aggregates leads to fiber atrophy and impaired regeneration.[xciv]^,[xcv]

During physiological stress such as endurance exercise or caloric restriction, autophagy is transiently upregulated to promote muscle fiber remodeling, improve mitochondrial efficiency, and mobilize intracellular substrates for energy production. This dynamic regulation involves key redox-sensitive signaling hubs, including AMPK and the Nrf2 pathway, which coordinate the transcriptional and post-translational activation of autophagy machinery in response to oxidative fluctuations.[xcvi] Notably, exercise-induced production of singlet oxygen and other reactive oxygen species may act as a hormetic trigger to fine-tune autophagic activity, enhancing long-term muscle resilience and metabolic health. Understanding the precise balance of autophagic signaling in skeletal muscle may therefore hold therapeutic relevance for age-related muscle decline and metabolic syndromes.

1.3.3.7.        Endocrine System: Hormone Regulation and Organelle Turnover

Within endocrine tissues, autophagy plays a dual role in general cellular maintenance and in regulating hormone synthesis and secretion. In peptide-producing cells such as those of the pituitary gland, a specialized autophagic process known as crinophagy enables the degradation of excess secretory granules, thus preventing hormone hypersecretion and contributing to hormonal balance. [xcvii]

In steroidogenic cells of the adrenal cortex and testes, autophagy selectively targets mitochondria and smooth endoplasmic reticulum, which are organelles central to steroid biosynthesis. This regulatory role ensures metabolic efficiency and prevents oxidative damage, especially under stress conditions.[xcviii]

Additionally, autophagy in endocrine tissues is modulated by oxidative signals, including ROS such as singlet oxygen, which can trigger redox-sensitive autophagy pathways to adjust hormonal output. Dysfunctional autophagy in endocrine glands has been associated with various pathologies, including diabetes, infertility, and hormone-secreting tumors, due to disrupted secretory or steroidogenic functions.^133,[xcix]

These findings suggest that targeted modulation of autophagy in endocrine tissues could represent a novel therapeutic approach to hormone-related disorders and metabolic diseases.

1.3.3.8.        Pregnancy: Placental Development and Immune Tolerance[c]

Autophagy plays a vital role in pregnancy by regulating trophoblast survival, supporting placental development, maintaining immune tolerance, and adapting to the dynamic metabolic demands of both mother and fetus. During early gestation, trophoblasts invade the uterine lining under low-oxygen conditions; here, autophagy facilitates cellular survival and promotes cytotrophoblast differentiation into the invasive phenotype essential for placental formation.

Autophagy also contributes to maternal–fetal immune tolerance by modulating inflammatory cytokine signaling, promoting tolerogenic dendritic cells, and regulating T cell activation. These effects reduce the risk of immune-mediated rejection of the semi-allogeneic fetus and help maintain immunological equilibrium at the maternal-fetal interface. [ci]

Additionally, under periods of maternal nutritional stress, autophagy enables intracellular recycling of macromolecules to maintain fetal nutrient supply and energy balance. Dysregulated autophagy, whether insufficient or excessive, has been implicated in various pregnancy complications, including preeclampsia, intrauterine growth restriction (IUGR), and gestational diabetes mellitus (GDM), highlighting its protective function in sustaining placental and fetal health. [cii]

1.3.3.9.        Liver: Metabolic Regulation and Tissue Regeneration

The liver relies on autophagy for maintaining metabolic balance, detoxification, and redox homeostasis. ^130,[ciii]  Through lipophagy, autophagy facilitates the degradation of intracellular lipid droplets, contributing to lipid turnover and preventing hepatic steatosis. Simultaneously, mitophagy ensures the removal of dysfunctional mitochondria, protecting hepatocytes from oxidative stress and limiting ROS production. This mitochondrial quality control also supports energy-efficient regeneration of liver tissue following injury, ensuring adequate ATP production while minimizing oxidative damage.^130,[civ] Dysregulation of hepatic autophagy has been implicated in liver diseases such as non-alcoholic fatty liver disease (NAFLD), alcoholic hepatitis, and fibrosis, underscoring its critical role in hepatocellular protection and regeneration.[cv]

1.3.4.             Concluding Synthesis: Autophagy as a Hormetic Mediator of Singlet Oxygen Signaling

Across a wide spectrum of tissues and physiological systems, autophagy emerges as a central regulatory process that integrates metabolic signals, oxidative cues, and stress adaptation. The evidence compiled in this chapter reveals a unifying theme: low-level oxidative stress, particularly that induced by singlet oxygen, can serve as a hormetic stimulus, activating autophagic pathways that support cellular renewal, immune modulation, and tissue repair (Figure 5).

In barrier tissues such as the skin and lungs, autophagy preserves epithelial integrity, controls inflammation, and enhances resilience to environmental insults. In skeletal and cardiac muscle, it maintains mitochondrial quality and metabolic homeostasis, particularly during physiological challenges like exercise or ischemia. In the liver, it coordinates lipid turnover and regeneration, while in the endocrine system and placenta, autophagy modulates hormonal synthesis and immune tolerance. Even during pregnancy, autophagy protects the maternal-fetal interface and contributes to placental development.

These diverse functions are governed by overlapping molecular mechanisms, including mitophagy, lipophagy, and redox-sensitive signaling via Nrf2, AMPK, and mTOR, yet are finely tuned to the needs of each tissue context. The dual role of autophagy in both cytoprotection and cell death is especially notable: the intensity and duration of singlet oxygen exposure may dictate whether autophagy serves a survival-promoting or pathological role, reflecting the delicate threshold between adaptive and maladaptive responses.

Understanding this context-dependence and threshold sensitivity is crucial for therapeutic modulation. Pharmacological or photo-induced activation of singlet oxygen may, under controlled conditions, be harnessed to stimulate beneficial autophagy, offering novel

treatment avenues in inflammatory, degenerative, metabolic, and fibrotic diseases.

In summary, autophagy is not merely a stress response- it is a homeostatic amplifier of hormetic signaling. Through its ability to decode singlet oxygen cues into tissue-specific adaptive programs, autophagy bridges environmental sensing with intracellular resilience, affirming its relevance as both a biomarker and target of oxidative medicine.

[i] Gems, D., & Partridge, L. (2008). Stress-response hormesis and aging:“that which does not kill us makes us stronger”. Cell metabolism, 7(3), 200-203.

[ii] Shaw, P., & Chattopadhyay, A. (2020). Nrf2–ARE signaling in cellular protection: Mechanism of action and the regulatory mechanisms. Journal of Cellular Physiology, 235(4), 3119-3130.

[iii] Baird, L., Llères, D., Swift, S., & Dinkova-Kostova, A. T. (2013). Regulatory flexibility in the Nrf2-mediated stress response is conferred by conformational cycling of the Keap1-Nrf2 protein complex. Proceedings of the National Academy of Sciences, 110(38), 15259-15264.

[iv] Liu, X., Ren, S., Li, Z., Hao, D., Zhao, X., Zhang, Z., & Liu, D. (2023). Sirt6 mediates antioxidative functions by increasing Nrf2 abundance. Experimental cell research, 422(1), 113409.

[v] Rezazadeh, S., Yang, D., Tombline, G., Simon, M., Regan, S. P., Seluanov, A., & Gorbunova, V. (2019). SIRT6 promotes transcription of a subset of NRF2 targets by mono-ADP-ribosylating BAF170. Nucleic acids research, 47(15), 7914-7928.

[vi]  Lu, S. C. (2013). Glutathione synthesis. Biochimica et Biophysica Acta (BBA)-General Subjects, 1830(5), 3143-3153.

[vii] Kensler, T. W., Wakabayashi, N., & Biswal, S. (2007). Cell survival responses to environmental stresses via the Keap1-Nrf2-ARE pathway. Annu. Rev. Pharmacol. Toxicol., 47(1), 89-116.

[viii] Conrad, M., & Pratt, D. A. (2019). The chemical basis of ferroptosis. Nature chemical biology, 15(12), 1137-1147.

[ix] Flohé, L., Toppo, S., & Orian, L. (2022). The glutathione peroxidase family: Discoveries and mechanism. Free Radical Biology and Medicine, 187, 113-122.

[x] Ma, Q. (2013). Role of nrf2 in oxidative stress and toxicity. Annual review of pharmacology and toxicology, 53(1), 401-426.

[xi] Grek, C. L., Zhang, J., Manevich, Y., Townsend, D. M., & Tew, K. D. (2013). Causes and consequences of cysteine S-glutathionylation. Journal of Biological Chemistry, 288(37), 26497-26504.

[xii] Telorack, M., Meyer, M., Ingold, I., Conrad, M., Bloch, W., & Werner, S. (2016). A glutathione-Nrf2-thioredoxin cross-talk ensures keratinocyte survival and efficient wound repair. PLoS genetics, 12(1), e1005800.

[xiii] (a) Ross, D., & Siegel, D. (2021). The diverse functionality of NQO1 and its roles in redox control. Redox Biology, 41, 101950. (b) Lee, W. S., Ham, W., & Kim, J. (2021). Roles of NAD (P) H: quinone oxidoreductase 1 in diverse diseases. Life, 11(12), 1301.

[xiv] (a) Waza, A. A., Hamid, Z., Ali, S., Bhat, S. A., & Bhat, M. A. (2018). A review on heme oxygenase-1 induction: is it a necessary evil. Inflammation Research, 67, 579-588. (b) Loboda, A., Damulewicz, M., Pyza, E., Jozkowicz, A., & Dulak, J. (2016). Role of Nrf2/HO-1 system in development, oxidative stress response and diseases: an evolutionarily conserved mechanism. Cellular and molecular life sciences, 73, 3221-3247. (c) Son, Y., Lee, J. H., Chung, H. T., & Pae, H. O. (2013). Therapeutic roles of heme oxygenase‐1 in metabolic diseases: curcumin and resveratrol analogues as possible inducers of heme oxygenase‐1. Oxidative medicine and cellular longevity, 2013(1), 639541.

[xv] Knoops, B., Argyropoulou, V., Becker, S., Ferté, L., & Kuznetsova, O. (2016). Multiple roles of peroxiredoxins in inflammation. Molecules and cells, 39(1), 60-64.

[xvi] Bafana, A., Dutt, S., Kumar, A., Kumar, S., & Ahuja, P. S. (2011). The basic and applied aspects of superoxide dismutase. Journal of Molecular Catalysis B: Enzymatic, 68(2), 129-138.

[xvii] Kirkman, H. N., & Gaetani, G. F. (2007). Mammalian catalase: a venerable enzyme with new mysteries. Trends in biochemical sciences, 32(1), 44-50.

[xviii] Lu, J., & Holmgren, A. (2014). The thioredoxin antioxidant system. Free radical biology and medicine, 66, 75-87.

[xix] Greeshma, M. V., Baidya, A., Mabalirajan, U., Madhunapantula, S. V., Thimmulappa, R. K., & Mahesh, P. A. (2024). Deciphering the role of 12/15-lipoxygenase in asthma: insights into mitochondrial dysfunction and therapeutic implications. Exploration of Asthma & Allergy, 2(6), 529-550.

[xx] Zhang, J., Zhang, M., Tatar, M., & Gong, R. (2025). Keap1-independent Nrf2 regulation: A novel therapeutic target for treating kidney disease. Redox Biology, 103593.

[xxi] Dong, H., Lyu, Y., Huang, C. Y., & Tsai, S. Y. (2025). Limiting cap-dependent translation increases 20S proteasomal degradation and protects the proteomic integrity in autophagy-deficient skeletal muscle. Autophagy, 21(6), 1212-1227.

[xxii] Kiang, J. G., & Tsokos, G. C. (1998). Heat shock protein 70 kDa: molecular biology, biochemistry, and physiology. Pharmacology & therapeutics, 80(2), 183-201.

[xxiii] Ameri, K., & Harris, A. L. (2008). Activating transcription factor 4. The international journal of biochemistry & cell biology, 40(1), 14-21.

[xxiv] (a) Richter-Landsberg, C., Wyttenbach, A., & Arrigo, A. P. (2009). The role of heat shock proteins during neurodegeneration in Alzheimer’s, Parkinson’s and Huntington’s disease. Heat shock proteins in neural cells, 81-99. (b) Zhang, N., Nao, J., Zhang, S., & Dong, X. (2024). Novel insights into the activating transcription factor 4 in Alzheimer’s disease and associated aging-related diseases: Mechanisms and therapeutic implications. Frontiers in Neuroendocrinology, 101144.

[xxv] (a) Bjørklund, G., Zou, L., Peana, M., Chasapis, C. T., Hangan, T., Lu, J., & Maes, M. (2022). The role of the thioredoxin system in brain diseases. Antioxidants, 11(11), 2161. (b) Cimini, A., Gentile, R., Angelucci, F., Benedetti, E., Pitari, G., Giordano, A., & Ippoliti, R. (2013). Neuroprotective effects of PrxI over‐expression in an in vitro human Alzheimer’s disease model. Journal of cellular biochemistry, 114(3), 708-715. (c) Zeng, X. S., Jia, J. J., Kwon, Y., Wang, S. D., & Bai, J. (2014). The role of thioredoxin-1 in suppression of endoplasmic reticulum stress in Parkinson disease. Free Radical Biology and Medicine, 67, 10-18.

[xxvi] (a) Ahsan, M. K., Lekli, I., Ray, D., Yodoi, J., & Das, D. K. (2009). Redox regulation of cell survival by the thioredoxin superfamily: an implication of redox gene therapy in the heart. Antioxidants & redox signaling, 11(11), 2741-2758. (b) Chong, C. R., Chan, W. P. A., Nguyen, T. H., Liu, S., Procter, N. E., Ngo, D. T., … & Horowitz, J. D. (2014). Thioredoxin-interacting protein: pathophysiology and emerging pharmacotherapeutics in cardiovascular disease and diabetes. Cardiovascular drugs and therapy, 28, 347-360.

[xxvii] Hao, X., Zhao, B., Towers, M., Liao, L., Monteiro, E. L., Xu, X., … & Zhang, R. (2024). TXNRD1 drives the innate immune response in senescent cells with implications for age-associated inflammation. Nature Aging, 4(2), 185-197.

[xxviii] Yang, Z. F., Drumea, K., Mott, S., Wang, J., & Rosmarin, A. G. (2014). GABP transcription factor (nuclear respiratory factor 2) is required for mitochondrial biogenesis. Molecular and cellular biology, 34(17), 3194-3201.

[xxix] (a) Gureev, A. P., Shaforostova, E. A., & Popov, V. N. (2019). Regulation of mitochondrial biogenesis as a way for active longevity: interaction between the Nrf2 and PGC-1α signaling pathways. Frontiers in genetics, 10, 435. (b) St-Pierre, J., Drori, S., Uldry, M., Silvaggi, J. M., Rhee, J., Jäger, S., … & Spiegelman, B. M. (2006). Suppression of reactive oxygen species and neurodegeneration by the PGC-1 transcriptional coactivators. Cell, 127(2), 397-408.

[xxx] Clements, C. M., McNally, R. S., Conti, B. J., Mak, T. W., & Ting, J. P. Y. (2006). DJ-1, a cancer-and Parkinson’s disease-associated protein, stabilizes the antioxidant transcriptional master regulator Nrf2. Proceedings of the National Academy of Sciences, 103(41), 15091-15096.

[xxxi] (a) Maiorino, M., Conrad, M., & Ursini, F. (2018). GPx4, lipid peroxidation, and cell death: discoveries, rediscoveries, and open issues. Antioxidants & redox signaling, 29(1), 61-74. (b) Lu, L., Oveson, B. C., Jo, Y. J., Lauer, T. W., Usui, S., Komeima, K., … & Campochiaro, P. A. (2009). Increased expression of glutathione peroxidase 4 strongly protects retina from oxidative damage. Antioxidants & redox signaling, 11(4), 715-724.

[xxxii] Roichman, A., Elhanati, S., Aon, M. A., Abramovich, I., Di Francesco, A., Shahar, Y., … & Cohen, H. Y. (2021). Restoration of energy homeostasis by SIRT6 extends healthy lifespan. Nature communications, 12(1), 3208.

[xxxiii] Cheng, J., Keuthan, C. J., & Esumi, N. (2023). The many faces of SIRT6 in the retina and retinal pigment epithelium. Frontiers in Cell and Developmental Biology, 11, 1244765.

[xxxiv] Palmeira, C. M., Teodoro, J. S., Amorim, J. A., Steegborn, C., Sinclair, D. A., & Rolo, A. P. (2019). Mitohormesis and metabolic health: The interplay between ROS, cAMP and sirtuins. Free Radical Biology and Medicine, 141, 483-491.

[xxxv] Kobayashi, E. H., Suzuki, T., Funayama, R., Nagashima, T., Hayashi, M., Sekine, H., … & Yamamoto, M. (2016). Nrf2 suppresses macrophage inflammatory response by blocking proinflammatory cytokine transcription. Nature communications, 7(1), 1-14.

[xxxvi] Guo, Z., Li, P., Ge, J., & Li, H. (2022). SIRT6 in aging, metabolism, inflammation and cardiovascular diseases. Aging and disease, 13(6), 1787.

[xxxvii] He, Y., Yang, G., Sun, L., Gao, H., Yao, F., Jin, Z., … & Lin, R. (2021). SIRT6 inhibits inflammatory response through regulation of NRF2 in vascular endothelial cells. International immunopharmacology, 99, 107926.

[xxxviii] Xu, W. D., Yang, C., & Huang, A. F. (2024). The role of Nrf2 in immune cells and inflammatory autoimmune diseases: a comprehensive review. Expert Opinion on Therapeutic Targets, 28(9), 789-806.

[xxxix] (a) Dodson, M., Shakya, A., Anandhan, A., Chen, J., Garcia, J. G., & Zhang, D. D. (2022). NRF2 and diabetes: the good, the bad, and the complex. Diabetes, 71(12), 2463-2476. (b) Vasileva, L. V., Savova, M. S., Amirova, K. M., Dinkova-Kostova, A. T., & Georgiev, M. I. (2020). Obesity and NRF2-mediated cytoprotection: Where is the missing link?. Pharmacological research, 156, 104760. (c) Li, S., Eguchi, N., Lau, H., & Ichii, H. (2020). The role of the Nrf2 signaling in obesity and insulin resistance. International journal of molecular sciences, 21(18), 6973.

[xl] (a) Zhang, Y., Wang, J., Wang, Y., & Lei, K. (2024). Nrf2/HO-1 signaling activation alleviates cigarette smoke-induced inflammation in chronic obstructive pulmonary disease by suppressing NLRP3-mediated pyroptosis. Journal of Cardiothoracic Surgery, 19(1), 58. (b) Audousset, C., McGovern, T., & Martin, J. G. (2021). Role of Nrf2 in disease: novel molecular mechanisms and therapeutic approaches–pulmonary disease/asthma. Frontiers in Physiology, 12, 727806.

[xli] Saha, S., Buttari, B., Profumo, E., Tucci, P., & Saso, L. (2022). A perspective on Nrf2 signaling pathway for neuroinflammation: a potential therapeutic target in Alzheimer’s and Parkinson’s diseases. Frontiers in cellular neuroscience, 15, 787258.

[xlii] Shi, T., & Dansen, T. B. (2020). Reactive oxygen species induced p53 activation: DNA damage, redox signaling, or both?. Antioxidants & Redox Signaling, 33(12), 839-859.

[xliii] Klotz, L. O., Briviba, K., & Sies, H. (1997). Singlet oxygen mediates the activation of JNK by UVA radiation in human skin fibroblasts. FEBS letters, 408(3), 289-291.

[xliv] Makino, T., Jinnin, M., Muchemwa, F. C., Fukushima, S., Kogushi‐Nishi, H., Moriya, C., … & Ihn, H. (2010). Basic fibroblast growth factor stimulates the proliferation of human dermal fibroblasts via the ERK1/2 and JNK pathways. British Journal of Dermatology, 162(4), 717-723.

[xlv] (a) Cuenda, A., & Rousseau, S. (2007). p38 MAP-kinases pathway regulation, function and role in human diseases. Biochimica et Biophysica Acta (BBA)-Molecular Cell Research, 1773(8), 1358-1375.

[xlvi] Klionsky, D. J. (2005). The molecular machinery of autophagy: unanswered questions. Journal of cell science, 118(Pt 1), 7. (b) Martindale, J. L., & Holbrook, N. J. (2002). Cellular response to oxidative stress: signaling for suicide and survival. Journal of cellular physiology, 192(1), 1-15.

[xlvii] (a) Wei, Y., Pattingre, S., Sinha, S., Bassik, M., & Levine, B. (2008). JNK1-mediated phosphorylation of Bcl-2 regulates starvation-induced autophagy. Molecular cell, 30(6), 678-688. (b) Yu, C., Minemoto, Y., Zhang, J., Liu, J., Tang, F., Bui, T. N., … & Lin, A. (2004). JNK suppresses apoptosis via phosphorylation of the proapoptotic Bcl-2 family protein BAD. Molecular cell, 13(3), 329-340.

[xlviii] (a) Zhou, J., Li, X. Y., Liu, Y. J., Feng, J., Wu, Y., Shen, H. M., & Lu, G. D. (2022). Full-coverage regulations of autophagy by ROS: from induction to maturation. Autophagy, 18(6), 1240-1255. (b) Przygoda, M., Bartusik-Aebisher, D., Dynarowicz, K., Cieślar, G., Kawczyk-Krupka, A., & Aebisher, D. (2023). Cellular mechanisms of singlet oxygen in photodynamic therapy. International Journal of Molecular Sciences, 24(23), 16890. (c) Liang, P., Kolodieznyi, D., Creeger, Y., Ballou, B., & Bruchez, M. P. (2020). Subcellular singlet oxygen and cell death: location matters. Frontiers in chemistry, 8, 592941.

[xlix] (a) Davies, K. J. (2000). Oxidative stress, antioxidant defenses, and damage removal, repair, and replacement systems. IUBMB life, 50(4‐5), 279-289. (b) Gao, Q. (2019). Oxidative stress and autophagy. Autophagy: biology and diseases: basic science, 179-198.

[l] (a) Kaminskyy, V. O., & Zhivotovsky, B. (2014). Free radicals in cross talk between autophagy and apoptosis. Antioxidants & redox signaling, 21(1), 86-102. (b) Yue, J., & López, J. M. (2020). Understanding MAPK signaling pathways in apoptosis. International journal of molecular sciences, 21(7), 2346.

[li] Kang, R., Zeh, H. J., Lotze, M. T., & Tang, D. J. C. D. (2011). The Beclin 1 network regulates autophagy and apoptosis. Cell Death & Differentiation, 18(4), 571-580.

[lii] Asgari, R., Yarani, R., Mohammadi, P., & Emami Aleagha, M. S. (2022). HIF-1α in the crosstalk between reactive oxygen species and autophagy process: a review in multiple sclerosis. Cellular and molecular neurobiology, 42(7), 2121-2129.

[liii] Romero, N. R., & Agostinis, P. (2014). Molecular mechanisms underlying the activation of autophagy pathways by reactive oxygen species and their relevance in cancer progression and therapy. In Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging (pp. 159-178). Academic Press.

[liv] Horan, M. P., Pichaud, N., & Ballard, J. W. O. (2012). Quantifying mitochondrial dysfunction in complex diseases of aging. Journals of Gerontology Series A: Biomedical Sciences and Medical Sciences, 67(10), 1022-1035.

[lv] Osellame, L. D., Rahim, A. A., Hargreaves, I. P., Gegg, M. E., Richard-Londt, A., Brandner, S., … & Duchen, M. R. (2013). Mitochondria and quality control defects in a mouse model of Gaucher disease—links to Parkinson’s disease. Cell metabolism, 17(6), 941-953.

[lvi] Morciano, G., Patergnani, S., Bonora, M., Pedriali, G., Tarocco, A., Bouhamida, E., … & Pinton, P. (2020). Mitophagy in cardiovascular diseases. Journal of clinical medicine, 9(3), 892.

[lvii] Miao, M. Q., Han, Y. B., & Liu, L. (2023). Mitophagy in metabolic syndrome. The Journal of Clinical Hypertension, 25(5), 397-403.

[lviii] Park, J. H., Ko, J., Park, Y. S., Park, J., Hwang, J., & Koh, H. C. (2017). Clearance of damaged mitochondria through PINK1 stabilization by JNK and ERK MAPK signaling in chlorpyrifos-treated neuroblastoma cells. Molecular neurobiology, 54, 1844-1857.

[lix] (a) Chen, M., Chen, Z., Wang, Y., Tan, Z., Zhu, C., Li, Y., … & Chen, Q. (2016). Mitophagy receptor FUNDC1 regulates mitochondrial dynamics and mitophagy. Autophagy, 12(4), 689-702. (b) Park, S. Y., & Koh, H. C. (2020). FUNDC1 regulates receptor-mediated mitophagy independently of the PINK1/Parkin-dependent pathway in rotenone-treated SH-SY5Y cells. Food and Chemical Toxicology, 137, 111163. (c) He, H., Huang, W., Xiong, L., Ma, C., Wang, Y., Sun, P., … & Wu, Y. (2024). FUNDC1-mediated mitophagy regulates photodamage independently of the PINK1/Parkin-dependent pathway. Free Radical Biology and Medicine, 225, 630-640.

[lx] Majeski, A. E., & Dice, J. F. (2004). Mechanisms of chaperone-mediated autophagy. The international journal of biochemistry & cell biology, 36(12), 2435-2444.

[lxi] Xiong, Y., Contento, A. L., Nguyen, P. Q., & Bassham, D. C. (2007). Degradation of oxidized proteins by autophagy during oxidative stress in Arabidopsis. Plant physiology, 143(1), 291-299.

[lxii] Kiffin, R., Christian, C., Knecht, E., & Cuervo, A. M. (2004). Activation of chaperone-mediated autophagy during oxidative stress. Molecular biology of the cell, 15(11), 4829-4840.

[lxiii] Cuervo, A. M., & Dice, J. F. (2000). Unique properties of lamp2a compared to other lamp2 isoforms. Journal of cell science, 113(24), 4441-4450.

[lxiv] Zhang, Q., Kang, R., Zeh, III, H. J., Lotze, M. T., & Tang, D. (2013). DAMPs and autophagy: cellular adaptation to injury and unscheduled cell death. Autophagy, 9(4), 451-458.

[lxv] (a) Deretic, V. (2021). Autophagy in inflammation, infection, and immunometabolism. Immunity, 54(3), 437-453. (b) Tsuji, Y., Kuramochi, M., Golbar, H. M., Izawa, T., Kuwamura, M., & Yamate, J. (2020). Acetaminophen-induced rat hepatotoxicity based on M1/M2-macrophage polarization, in possible relation to damage-associated molecular patterns and autophagy. International Journal of Molecular Sciences, 21(23), 8998. (c) Levy, J. M. M., Towers, C. G., & Thorburn, A. (2017). Targeting autophagy in cancer. Nature Reviews Cancer, 17(9), 528-542.

[lxvi] Levine, B., Mizushima, N., & Virgin, H. W. (2011). Autophagy in immunity and inflammation. Nature, 469(7330), 323-335.

[lxvii] Deretic, V., Saitoh, T., & Akira, S. (2013). Autophagy in infection, inflammation and immunity. Nature Reviews Immunology, 13(10), 722-737.

[lxviii] Moore, M. N. (2020). Lysosomes, autophagy, and hormesis in cell physiology, pathology, and age-related disease. Dose-Response, 18(3), 1559325820934227.

[lxix] García-Prat, L., Martínez-Vicente, M., Perdiguero, E., Ortet, L., Rodríguez-Ubreva, J., Rebollo, E., … & Muñoz-Cánoves, P. (2016). Autophagy maintains stemness by preventing senescence. Nature, 529(7584), 37-42.

[lxx] Hara, T., Nakamura, K., Matsui, M., Yamamoto, A., Nakahara, Y., Suzuki-Migishima, R., … & Mizushima, N. (2006). Suppression of basal autophagy in neural cells causes neurodegenerative disease in mice. Nature, 441(7095), 885-889.

[lxxi] Zapata-Muñoz, J., Villarejo-Zori, B., Largo-Barrientos, P., & Boya, P. (2021). Towards a better understanding of the neuro-developmental role of autophagy in sickness and in health. Cell Stress, 5(7), 99.

[lxxii] Nixon, R. A. (2013). The role of autophagy in neurodegenerative disease. Nature medicine, 19(8), 983-997.

[lxxiii] Tomoda, T., Yang, K., & Sawa, A. (2020). Neuronal autophagy in synaptic functions and psychiatric disorders. Biological psychiatry, 87(9), 787-796.

[lxxiv] Sil, P., Wong, S. W., & Martinez, J. (2018). More than skin deep: autophagy is vital for skin barrier function. Frontiers in immunology, 9, 1376.

[lxxv] Jeong, D., Qomaladewi, N. P., Lee, J., Park, S. H., & Cho, J. Y. (2020). The role of autophagy in skin fibroblasts, keratinocytes, melanocytes, and epidermal stem cells. Journal of Investigative Dermatology, 140(9), 1691-1697.

[lxxvi] Richmond, J. M., & Harris, J. E. (2014). Immunology and skin in health and disease. Cold Spring Harbor perspectives in medicine, 4(12), a015339.

[lxxvii] Pivarcsi, A., Nagy, I., & Kemeny, L. (2005). Innate immunity in the skin: how keratinocytes fight against pathogens. Current immunology reviews, 1(1), 29-42.

[lxxviii] Davidson, S., Coles, M., Thomas, T., Kollias, G., Ludewig, B., Turley, S., … & Buckley, C. D. (2021). Fibroblasts as immune regulators in infection, inflammation and cancer. Nature Reviews Immunology, 21(11), 704-717.

[lxxix] Zhang, H., Xia, M., Li, H., Zeng, X., Jia, H., Zhang, W., & Zhou, J. (2025). Implication of Immunobiological Function of Melanocytes in Dermatology. Clinical Reviews in Allergy & Immunology, 68(1), 30.

[lxxx] Jeong, D., Qomaladewi, N. P., Lee, J., Park, S. H., & Cho, J. Y. (2020). The role of autophagy in skin fibroblasts, keratinocytes, melanocytes, and epidermal stem cells. Journal of Investigative Dermatology, 140(9), 1691-1697.

[lxxxi] Ren, H., Zhao, F., Zhang, Q., Huang, X., & Wang, Z. (2022). Autophagy and skin wound healing. Burns & trauma, 10, tkac003.

[lxxxii] Li, X., Wu, J., Sun, X., Wu, Q., Li, Y., Li, K., … & Chen, H. (2020). Autophagy reprograms alveolar progenitor cell metabolism in response to lung injury. Stem Cell Reports, 14(3), 420-432.

[lxxxiii] de la Vega, M. R., Dodson, M., Gross, C., Mansour, H. M., Lantz, R. C., Chapman, E., … & Zhang, D. D. (2016). Role of Nrf2 and autophagy in acute lung injury. Current pharmacology reports, 2, 91-101.

[lxxxiv] Yin, X., Xin, H., Mao, S., Wu, G., & Guo, L. (2019). The role of autophagy in sepsis: protection and injury to organs. Frontiers in physiology, 10, 1071.

[lxxxv] Barnes, P. J., Baker, J., & Donnelly, L. E. (2022). Autophagy in asthma and chronic obstructive pulmonary disease. Clinical Science, 136(10), 733-746.

[lxxxvi] Mizumura, K., Maruoka, S., Shimizu, T., & Gon, Y. (2018). Autophagy, selective autophagy, and necroptosis in COPD. International journal of chronic obstructive pulmonary disease, 3165-3172.

[lxxxvii] Araya, J., Kojima, J., Takasaka, N., Ito, S., Fujii, S., Hara, H., … & Kuwano, K. (2013). Insufficient autophagy in idiopathic pulmonary fibrosis. American Journal of Physiology-Lung Cellular and Molecular Physiology, 304(1), L56-L69.

[lxxxviii] Patel, A. S., Lin, L., Geyer, A., Haspel, J. A., An, C. H., Cao, J., … & Morse, D. (2012). Autophagy in idiopathic pulmonary fibrosis. PloS one, 7(7), e41394.

[lxxxix] McAlinden, K. D., Deshpande, D. A., Ghavami, S., Xenaki, D., Sohal, S. S., Oliver, B. G., … & Sharma, P. (2019). Autophagy activation in asthma airways remodeling. American journal of respiratory cell and molecular biology, 60(5), 541-553.

[xc] Liu, C., Liu, Y., Chen, H., Yang, X., Lu, C., Wang, L., & Lu, J. (2023). Myocardial injury: where inflammation and autophagy meet. Burns & Trauma, 11, tkac062.

[xci] Alcalai, R., Arad, M., Wakimoto, H., Yadin, D., Gorham, J., Wang, L., … & Seidman, C. E. (2021). LAMP2 cardiomyopathy: consequences of impaired autophagy in the heart. Journal of the American Heart Association, 10(17), e018829.

[xcii] Liu, Y., Wang, Y., Bi, Y., Zhao, Z., Wang, S., Lin, S., … & Mao, J. (2023). Emerging role of mitophagy in heart failure: from molecular mechanism to targeted therapy. Cell Cycle, 22(8), 906-918.

[xciii] Shen, Y., Liu, X., Shi, J., & Wu, X. (2019). Involvement of Nrf2 in myocardial ischemia and reperfusion injury. International journal of biological macromolecules, 125, 496-502.

[xciv] Chen, X., Ji, Y., Liu, R., Zhu, X., Wang, K., Yang, X., … & Sun, H. (2023). Mitochondrial dysfunction: roles in skeletal muscle atrophy. Journal of Translational Medicine, 21(1), 503.

[xcv] Li, P., Ma, Y., Yu, C., Wu, S., Wang, K., Yi, H., & Liang, W. (2021). Autophagy and aging: Roles in skeletal muscle, eye, brain and hepatic tissue. Frontiers in Cell and Developmental Biology, 9, 752962.

[xcvi] Ferraro, E., Giammarioli, A. M., Chiandotto, S., Spoletini, I., & Rosano, G. (2014). Exercise-induced skeletal muscle remodeling and metabolic adaptation: redox signaling and role of autophagy. Antioxidants & redox signaling, 21(1), 154-176.

[xcvii] Weckman, A., Di Ieva, A., Rotondo, F., Syro, L. V., Ortiz, L. D., Kovacs, K., & Cusimano, M. D. (2014). Autophagy in the endocrine glands. J Mol Endocrinol, 52(2), R151-R163.

[xcviii] (a) Afzal, A., Zhang, Y., Afzal, H., Saddozai, U. A. K., Zhang, L., Ji, X. Y., & Khawar, M. B. (2024). Functional role of autophagy in testicular and ovarian steroidogenesis. Frontiers in Cell and Developmental Biology, 12, 1384047. (b) Xu, R., Wang, F., Zhang, Z., Zhang, Y., Tang, Y., Bi, J., … & Tang, Z. (2023). Diabetes‐induced autophagy dysregulation engenders testicular impairment via oxidative stress. Oxidative medicine and cellular longevity, 2023(1), 4365895.

[xcix] (a) Kong, X., Wang, X., Xia, Q., Hu, Q., Yu, W., Huang, Q., … & Yu, J. (2025). Unveiling the nexus between environmental exposures and testicular damages: revelations from autophagy and oxidative stress imbalance. Cell Death Discovery, 11(1), 258. (b) Jung, H. S., & Lee, M. S. (2010). Role of autophagy in diabetes and mitochondria. Annals of the New York Academy of Sciences, 1201(1), 79-83.

[c] Zhao, X., Jiang, Y., Jiang, T., Han, X., Wang, Y., Chen, L., & Feng, X. (2020). Physiological and pathological regulation of autophagy in pregnancy. Archives of Gynecology and Obstetrics, 302(2), 293-303.

[ci] Chen, H., Chen, Y., & Zheng, Q. (2024). The regulated cell death at the maternal-fetal interface: beneficial or detrimental?. Cell Death Discovery, 10(1), 100.

[cii] Zhou, P., Wang, J., Wang, J., & Liu, X. (2024). When autophagy meets placenta development and pregnancy complications. Frontiers in Cell and Developmental Biology, 12, 1327167.

[ciii] Wang, Y., Singh, R., Xiang, Y., & Czaja, M. J. (2010). Macroautophagy and chaperone‐mediated autophagy are required for hepatocyte resistance to oxidant stress. Hepatology, 52(1), 266-277.

[civ] Xu, F., Hua, C., Tautenhahn, H. M., Dirsch, O., & Dahmen, U. (2020). The role of autophagy for the regeneration of the aging liver. International journal of molecular sciences, 21(10), 3606.

[cv] (a) Cursio, R., Colosetti, P., Codogno, P., Cuervo, A. M., & Shen, H. M. (2015). The role of autophagy in liver diseases: mechanisms and potential therapeutic targets. BioMed Research International, 2015, 480508. (b) Ruart, M., Chavarria, L., Campreciós, G., Suárez-Herrera, N., Montironi, C., Guixé-Muntet, S., … & Hernández-Gea, V. (2019). Impaired endothelial autophagy promotes liver fibrosis by aggravating the oxidative stress response during acute liver injury. Journal of hepatology, 70(3), 458-469.